1. Field of Invention
This invention relates to novel 1-carba(1-dethia)-3-cephem-4-carboxylic and 3-cephem-carboxylic acid derivatives which contain unique 3,4-dioxo-1-cyclobutenyl moieties in the C-3 position. The compounds of the instant invention were found to possess potent antibacterial activity. Thus, in another aspect, this invention relates to their antibiotic use and pharmaceutical compositions. Also included within the scope of the present invention are useful intermediates for the synthesis of said antibiotics.
2. Nomenclature and Numbering
Formula I below represents compounds of the present invention; the numbering therein shows the convention used in this application ##STR3## and follows the most widely system used in the art. In formula I, a class of compounds having X as sulfur will be referred to as 3-cephem-carboxylic acids, or simply as cephalosporins. On the other hand when X is CH.sub.2, the class will be named as 1-carba(1-dethia)-3-cephem-4-carboxylic acids, or simply as 1-carbacephalosporins. defined hereinbelow.
3. Description of Related Art
In the antibiotic arts, there has long been a need for new and effective antibiotic compounds. Due to rapid changes in pathogens, for which treatment with the antibiotic compounds are required, the older and more used antibiotics often become either ineffective or significantly less effective against the pathogens. Effective antibiotics are therefore in constant demand to replace the older and more used antibiotics.
Because of the above mentioned long felt need in this art for more potent and effective antibiotics, many cephalosporin compounds and their derivatives, including 1-carbacephalosporins have been synthesized and tested for appropriate antibiotic properties. One hypothesis leading toward more potent antibacterial agents is to attach electron withdrawing groups on the C-3 positions with hopes of increasing the acylating potential of the .beta.-lactams, such as the prototypes cefaclor and loracarbef having the following structure. ##STR4##
Examples of other compounds, which have C-3 electron withdrawing substituents appear in the following patents and printed publications:
(a) European Application 154,253 published on Feb. 20, 1984 discloses carbacephalosporins of the formula ##STR5## wherein R.sup.11 is a lower alkylsulfonyloxy, unsubstituted or substituted arylsulfonyloxy, azido, cyano, carbamoyloxy, unsubstituted or substituted heterocyclic thio, unsubstituted or substituted lower alkylthio, or unsubstituted or substituted arylthio group; R.sup.12 is a group represented by the formula in which R.sup.13 is an unsubstituted or substituted phenyl, or 2-aminothiazolyl group, or a group represented by the formula ##STR6## in which R.sup.14 is an unsubstituted or substituted lower alkyl group.
(b) Cromwell et al., in the Journal of Medicinal Chemistry, 32, p. 2436 (1989) discloses, inter alia, other 3-sulfonyl-1-carbacephalosporins represented by the general formula ##STR7## wherein R.sup.15 is cyclopropyl, 2-thienyl, 3-pyridyl, and 4-(3,5-Me.sub.2)isoxazolyl.
(c) European Application 327,239 published on Jan. 25, 1988, discloses, inter alia, 1-carbacephalosporins of the formula ##STR8## wherein the radical EQU N.tbd.Y
is a quaternary ammonium group that may be acyclic, cyclic, or a combination of the two, and may contain one or more additional hetero atoms selected from nitrogen, sulfur and oxygen; R.sup.16 is hydrogen, C.sub.1-4 alkyl, or a carboxy-substituted alkyl or cyloalkyl group represented by the formula ##STR9## wherein R.sup.20 and R.sup.21 independently are hydrogen or C.sub.1-3 alkyl, or R.sup.20 and R.sup.21 taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, and n is 0-3.
(d) A number of cephalosporins with heterocycles directly attached to the C-3 position have been reported, for example:
(i) U.S. Pat. No. 4,508,717 issued on Apr. 2, 1985 to Berger et al. discloses, inter alia, cephlosporins of the formula ##STR10## in which R.sup.24 is methyl, carboxymethyl, carbamoylmethyl, benzyl or allyl radical; R.sup.p, R.sup.q, and R.sup.s are hydrogen, or alternatively R.sup.p is carboxy and R.sup.q and R.sup.s which are identical or different, are hydrogen atoms or alkyl radicals, or together form an alkylene radical;
(ii) U.S. Pat. No. 4,496,560 issued on Jan. 29, 1985 to Farge relates, inter alia, to compounds of the formula. ##STR11## in which R.sup.26 represents a radical selected from thienyl, furyl, 1,3-dithiol-2-on-4-yl, phenyl, p-hydroxyphenyl, phenoxy and dichlorophenylthio; and R.sup.25 is hydrogen, phenyl, alkylthio, alkylamino, etc.
(iii) Fahey et al. in the Journal of Medicinal Chemistry, 19, 4, p 562 (1976) disclose cephalosporins of the formula ##STR12## in which R.sup.28 is hydrogen or diphyenylethyl; and R.sup.27 is a radical selected from the group ##STR13##
(iv) Sugawara et al. in Chem. Pharm. Bull., 28, 7, p 2116 (1980) disclose, inter alia, compounds of formula ##STR14## in which R.sup.29 equals dimethylamino, 1-morpholino, methyl, phenyl, acetylamino, N-methyl-N-acetylamino and methylamino; and R.sup.28 is hydrogen or diphenylmethyl.
(v) More recently, at the 200th American Chemical Society meeting held in Washington D.C., Aug. 26-31, 1990, Hornback et al. have disclosed, inter alia, compounds of formula IV' ##STR15## in which R.sup.30 is a radical selected from the group ##STR16##
(e) Compounds of formula III, in which X is S or CH.sub.2 ; and R.sup.9 and R.sup.8 are amino and carboxy protecting groups, respectively, have already been described as useful intermediates leading to a variety of cephalosporin related antibiotics. The synthesis of formula III compounds, wherein X is sulfur, has been disclosed by Farina et al. in The Journal of Organic Chemistry, 54, 20, p. 4963 (1989). European Patent Application No. 211,540 published on Feb. 25, 1987 discloses the optically active form of 1-carbacephalosporins of formula III. Furthermore, Hatanaka et al. in Tetrahedron Letters, 24, 44, p. 4837 (1983) disclose the synthesis of a racemic C-3 hydroxyl 1-carbacephalosporin of formula II, a precursor to a corresponding racemic triflate of formula III.
The utility of compounds of formula III has been demonstrated by Farina et al., in Tetrahedron Letters, 29, 47, p 6043 (1988), and Cook et al., in The Journal of Organic Chemistry, 54, p. 5828 (1989), wherein the authors took tri-n-butylstannes, n-Bu.sub.3 SnR.sup.7, in the ##STR17## presence of a palladium (0) catalyst to transfer a variety of R.sup.7 radicals to the C-3 positions of compounds of formula III (Scheme I). Examples of R.sup.7 radicals include alkyl, alkenyl, alkynyl, and aryl.